Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States of America; Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, United States of America.
Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States of America.
Neurobiol Dis. 2024 Oct 15;201:106673. doi: 10.1016/j.nbd.2024.106673. Epub 2024 Sep 20.
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown. To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.
脊髓小脑共济失调 1 型（SCA1）是一种显性遗传性和致命的神经退行性疾病，由 ATAXIN-1（ATXN1）基因中 CAG 重复序列的异常扩增引起。病理学研究发现，脑桥和脊髓中的运动神经元（MNs）功能障碍和丧失，这被认为通过影响 SCA1 患者的吞咽和呼吸而导致过早死亡。然而，MN 发病机制的分子和细胞机制仍不清楚。为了在人类 MNs 中研究 SCA1 发病机制，我们将源自 SCA1 患者及其未受影响的兄弟姐妹的诱导多能干细胞（iPSCs）分化为 MNs。我们检查了祖细胞的增殖、突起生长、SCA1 MNs 的自发性和谷氨酸诱导的钙活性，以研究发病机制的细胞机制。然后使用 RNA 测序来鉴定 iPSC 衍生的 MN 祖细胞（pMNs）和 MNs 中的转录变化，这些变化可能是 SCA1 MNs 中功能变化的基础。我们发现自发性和诱发钙活性显著降低，并确定 SCA1 MNs 中钙信号调节基因的失调。这些结果表明，扩增的 ATXN1 导致人类 MNs 中功能性钙信号传导障碍。
